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Intratumoral patterns of clonal evolution in gliomas

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Abstract

Few studies have explored the patterns of clonal evolution in gliomas. Here, we investigate the cytogenetic patterns of intratumoral clonal evolution of gliomas and their impact on tumor histopathology and patient survival. Cytogenetic analysis of 90 gliomas was performed in individual tumor cells (>200 cells/tumor) using multicolor (N = 16 probes) interphase—FISH. Overall, chromosome gains were more frequent than chromosome losses. Gains of chromosome 7 and/or EGFR amplification were detected in 91% of the cases, whereas del(9p21) (77%) and del(10q23) (78%) were the most frequent chromosome losses. Virtually, all cases (99%) showed ≥2 tumor cell clones, with higher numbers among high- versus low-grade gliomas (p = 0.001). Nine different cytogenetic patterns were found in the ancestral tumor clones. In most gliomas, ancestral clones showed abnormalities of chromosome 7, 9p, and/or 10q and cytogenetic evolution consisted of acquisition of additional abnormalities followed by tetraploidization. Conversely, early tetraploidization was associated with low-grade astrocytomas—2/3 pilocytic and 3/6 grade II diffuse astrocytomas—and combined loss of 1p36/19q13 with oligodendrogliomas, respectively; both aberrations were associated with a better patient outcome (p = 0.03). Overall, our results support the existence of different pathways of intratumoral evolution in gliomas

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Acknowledgments

This work has been partially supported by grants from FCT (Portuguese Foundation for Science and Technology, PhD fellowships SFRH/BD/11820/2003 and SFRH/BD/23086/2005), FCG (Portuguese Calouste Gulbenkian Foundation, Project Ref. 68708) and Spanish Network of Cancer Research Centers (RD06/0020/0035; RTICC; Instituto de Salud Carlos III, Ministerio of Science and Innovation, Madrid, Spain).

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Author notes

  1. Ana Luísa Vital

    Present address: PhD Programme on Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517, Coimbra, Portugal

Authors and Affiliations

  1. Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Ana Luísa Vital, Inês Crespo & Maria Celeste Lopes

  2. Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Ana Luísa Vital, Inês Crespo & Maria Celeste Lopes

  3. Research Unit of the University Hospital of Salamanca, Paseo San Vicente 58-182, Salamanca, Spain

    Maria Dolores Tabernero

  4. Centre for Cancer Research (CIC IBMCC-CSIC/USAL) and Department of Medicine, University of Salamanca, Salamanca, Spain

    Maria Dolores Tabernero & Alberto Orfao

  5. IECSCYL, Salamanca, Spain

    Maria Dolores Tabernero

  6. Neuropathology Laboratory, Neurology Service, University Hospital of Coimbra, Coimbra, Portugal

    Olinda Rebelo

  7. Neurosurgery Service, University Hospital of Coimbra, Coimbra, Portugal

    Hermínio Tão & Fernando Gomes

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  1. Ana Luísa Vital
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Correspondence to Maria Dolores Tabernero.

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Maria Celeste Lopes and Alberto Orfao: both authors have equally contributed to this work and they should be both considered as last authors.

Electronic supplementary material

Supplementary Fig. 1

Detailed information about the hypothetical pathways of intratumoral clonal evolution of gliomas (n = 90) defined on the basis of the cytogenetic patterns detected for the 16 different chromosome probes analyzed. In this figure, different colored rectangles (and horizontal bars) identify the ancestral tumor cell clone and the subsequent second, third, and fourth clones reflecting more advanced stages of clonal evolution, respectively; all cases in the second and subsequent third and fourth clones also shared the abnormalities of the previous clones. For each cytogenetic pattern its frequency among all gliomas analyzed, is shown. According to the International System for Human Cytogenetic Nomenclature ISCN 2005 Cytogenetic nomenclature for iFISH correspond to: nul9p: nuc ish 9p21 (p16,INK4Ax0; p14,ARFx0; p15,INK4Bx0); −1p: nuc ish 1p36 (TP73x1; EGTL3x1); −1q: nuc ish 1q25 (ANGPTL1x1; ABL2x1); −7p: nuc ish 7p12 (EGFRx1); −7: nuc ish 7cen (D7Z1x1); −7q: nuc ish 7q31 (ELNx1); −9p: nuc ish 9p21 (p16,INK4Ax1; p14,ARFx1; p15,INK4Bx1); −9: nuc ish 9cen (9p11q11x1); −9q: nuc ish 9q34 (ABLx1); −10: nuc ish 10cen (10p11.1q11.1x1); −10q: nuc ish 10q23 (PTENx1); −13q: nuc ish 13q14 (RB1 x1); −17p: nuc ish 17p13 (TP53x1); −19p: nuc ish 19p13 (ZNF44x1; ZK1x1; MAFFZB1x1); −19q: nuc ish 19q13 (GLTSCR1x1; GLTSCR2x1; CRXx1); −22q: nuc ish 22q11.2 (BCRx1); +1p: nuc ish 1p36 (TP73x3; EGTL3x3);+1q: nuc ish 1q25 (ANGPTL1x3; ABL2x3);+7p: nuc ish 7p12 (EGFRx3); +7: nuc ish 7cen (D7Z1x3); +7q: nuc ish 7q31 (ELNx3); +9p: nuc ish 9p21 (p16,INK4Ax3; p14,ARFx3; p15,INK4Bx3); +9: nuc ish 9cen (9p11q11x3); +9q: nuc ish 9q34 (ABLx3); +10: nuc ish 10cen (10p11.1q11.1x3); +10q: nuc ish 10q23 (PTENx3); +13q: nuc ish 13q14 (RB1x3); +17p: nuc ish 17p13 (TP53x3); +19p: nuc ish 19p13 (ZNF44x3; ZK1x3; MAFFZB1x3); +19q: nuc ish 19q13 (GLTSCR1x3; GLTSCR2x3; CRXx3);+22q: nuc ish 22q11.2 (BCRx3); amp7p: nuc ish amp (EGFR) (JPEG 1941 kb)

Supplementary Table 1

Commercially available interphase fluorescence in situ hybridization (iFISH) probes directed against specific gene locus which were systematically applied to the study of glioma tumors (DOC 34 kb)

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Vital, A.L., Tabernero, M.D., Crespo, I. et al. Intratumoral patterns of clonal evolution in gliomas. Neurogenetics 11, 227–239 (2010). https://doi.org/10.1007/s10048-009-0217-x

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